Glioblastoma (GBM) is the most frequent form of malignant brain tumors. Patients with this disease face a poor prognosis of only 14 to 16 months from the time of diagnosis, despite aggressive treatment protocols. Among the main challenges when treating this condition, is the presence of infiltrated tumor cells located behind the blood-brain-barrier (BBB), a natural protection mechanism that restricts access to the brain for compounds present in the blood. As a result, systemically delivered drugs often fail to reach their targets, causing the tumor to recur after treatment. Thus, techniques that can safely and transiently open the BBB to facilitate the delivery of therapeutic agents to the brain represent a major interest for this disease as well as for other brain pathologies. The hosting institution in the present application, the laboratory of Pr. Max Wintermark from the Department of Radiology at the University of Stanford, US, is using focused ultrasound (FUS) with systemically injected microbubbles to create transient openings of the BBB. The technique is safe and already used in the clinic for various conditions. Magnetic Resonance Imaging (MRI) can additionally be used to locate specific regions or lesions in the brain and guide the FUS delivery, a method referred to as Magnetic Resonance guided Focused Ultrasounds (MRgFUS). Pr. Wintermark has received a NIH grant to apply MRgFUS to open the BBB and test its ability to improve the efficacy of immunotherapy in preclinical models of GBM. The first aim of the researcher mobility program will therefore be to take part in the setup of an innovative leading edge platform for preclinical MRgFUS by bringing expertise in MRI sequences development, and contributing to the optimization of protocols for BBB opening through interactions with experts in the field. The second aim will be to assess if this technique can improve the efficacy of an experimental immunotherapy treatment for GBM. Another challenge related to the treatment of GBM is the difficulty to find therapeutic molecules that can selectively target cancer cells and minimize side effects to healthy tissues. In this respect, the applicant has been involved in collaborative studies with the group of Pr. Tambet Teesalu at the University of Tartu, Estonia, that specializes in the development of therapeutics loaded nanoparticles functionalized with tumor homing peptides. In preliminary studies, a unique bispecific peptide was found that selectively targets tumor-associated extracellular matrix, homes to GBM tissue and penetrates the tumor with high specificity. The third aim of the researcher mobility program will be to test if the delivery and efficacy of functionalized nanoparticles can also be improved by MRgFUS in preclinicalmodels of GBM. The final aim of the program will be to establish a strong partnership and collaborative projects between Luxembourg research groups and research groups at the University of Stanford and the University of Tartu in the area of local treatment of brain diseases. Upon completion of the research program, it is expected that the applicant will have developed the necessary skills to establish in Luxembourg techniques for drug delivery across the BBB using MRgFUS, and initiate a research program for images guided local treatment of brain conditions. Such techniques will benefit several groups inLuxembourg involved in research on brain tumors and neurodegenerative diseases. The possibility to safely and efficiently deliver drugs to the brain is expected to be a key enabler of future personalized treatment of brain conditions and is therefore clearly aligned with the strategic directions set for the research in Luxembourg. The promises of both immunotherapy and functionalized nanoparticles treatments bear the potential of translational applications and early stage clinical trials in the near future.
|Effective start/end date
|1/08/18 → 31/07/19
- FNR - Fonds National de la Recherche: €150,000.00
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